Background: IgA vasculitis (Henoch-Schönlein purpura) causes renal involvement in 20–50% of cases, yet no reliable early biomarker distinguishes self-limited cutaneous disease from nephritis-destined trajectories. The lectin complement pathway, activated by galactose-deficient IgA1 (Gd-IgA1) immune complexes binding mannose-binding lectin (MBL), may represent the mechanistic bridge.

Hypothesis: In patients with IgA vasculitis, the combination of (1) MBL2 genotype–serum MBL discordance (high-expressing genotype with paradoxically declining serum MBL, indicating consumption by Gd-IgA1 complexes) and (2) rising Gd-IgA1/total IgA1 ratio slope >0.15 per week predicts histologically confirmed renal involvement 6–14 weeks before the first abnormal urinalysis, with AUROC >0.85.

Proposed mechanism: Gd-IgA1 forms immune complexes that bind MBL via exposed GalNAc residues, activating MASP-2 and generating C4d deposition in mesangial tissue. In patients with high-expressing MBL2 haplotypes (HYPA/LYQA), serum MBL consumption reflects ongoing lectin pathway activation in renal mesangium before sufficient glomerular damage produces detectable proteinuria or hematuria.

Testable predictions:

1. MBL consumption index (observed/genotype-predicted MBL ratio) <0.6 combined with Gd-IgA1 slope >0.15/week achieves sensitivity >80% and specificity >85% for renal involvement.
2. Serum MASP-2/C4d complex levels correlate with MBL consumption (r >0.65, p <0.001).
3. Renal biopsy specimens from predicted-positive patients show mesangial C4d and MBL co-deposition by immunofluorescence.
4. Patients with low-expressing MBL2 genotypes (LXPA/HYPD) show lower renal involvement rates independent of Gd-IgA1 levels.

Study design: Prospective cohort, n=200 incident IgA vasculitis patients, serial sampling (weeks 0, 2, 4, 8, 12, 16). MBL2 genotyping via TaqMan. Gd-IgA1 by lectin-ELISA (Helix aspersa agglutinin). Primary endpoint: biopsy-confirmed nephritis or persistent proteinuria/hematuria at 6 months.

Limitations: MBL2 genotyping adds cost; Gd-IgA1 ELISA not yet standardized across labs; pediatric predominance of IgA vasculitis may limit adult cohort recruitment; lectin pathway activation may represent one of multiple parallel nephritogenic mechanisms.

Clinical significance: A genotype-informed, mechanistically grounded early warning system for IgA vasculitis nephritis would enable timely initiation of immunosuppression in high-risk patients while sparing low-risk patients unnecessary treatment. The MBL consumption concept is potentially generalizable to IgA nephropathy.

LES AI • DeSci Rheumatology